A major component of the plaques and tangles found in Alzheimer's disease is the betaA/4 protein which is derived from the amyloid precursor protein (APP) by proteolytic cleavage. The specific events leading to this deposition are presently unknown but different isoforms of APP may play a role in this phenomenon. A feature that distinguishes APP isoforms is the presence or absence of a Kunitz-type serine protease inhibitor (KPI) domain in the extracellular amino terminal portion of the molecule. One APP isoform lacking the KPI domain, is a 695 amino acid protein (APP-695) largely restricted in its expression to the central nervous system. At the mRNA level, the APP gene produces multiple transcripts in the human and rodent central nervous system. The most abundant species of APP mRNA expressed in the CNS of rodents and other lower mammals lacks sequences encoding the KPI domain, while KPI-containing forms of APP message, such as APP-751, are expressed at relatively higher levels in the human brain. Our work shows that the ubiquitous, KPI-containing forms of APP mRNA appear to accumulate during aging of the human and rat CNS, and increases in the APP-751/APP-695 ratio are associated with Alzheimer's disease in affected brain regions. In addition, switching of APP RNA splicing to APP-695 in cognitively impaired, aged rats can be regulated by exogenous administration of nerve growth factor (NGF), which also reverses spatial memory impairments associated with aging in these rats. The results suggest that abnormal expression of different isoforms of the APP protein may be important in the etiology of Alzheimer's disease.